This white paper provides an overview of creating an integrated drug development plan, overcoming common development challenges and devising strategies that increase the likelihood of delivering a new, approved medicine to patients.

1. CREATING A COMPREHENSIVE
DRUG DEVELOPMENT PLAN
Less than about 10% of novel compounds that enter initial Phase I clinical trials will obtain
regulatory approval for marketing. Therapeutic efficacy and safety of a new compound are necessary,
but not sufficient to assure cost-effective development, or successful launch and commercialization.
As an expensive and complex process, drug development requires the coordinated efforts of diverse
disciplines, including nonclinical, clinical, regulatory and commercial experts. On the path to market,
pharmaceutical and biotechnology companies face many obstacles and potential pitfalls, which can
cause costly delays or stop progress entirely. This white paper provides an overview of creating an
integrated drug development plan, an important tool for identifying development challenges and
devising strategies that increase the likelihood of delivering a new, approved medicine to patients.
What Is the Role of a Comprehensive Development Strategy?
When starting a new drug program, experienced pharmaceutical companies devote considerable effort to
create a comprehensive development strategy. This plan provides a detailed roadmap for advancing a new
compound from the lab though each stage of development, ultimately arriving at the envisioned marketed
drug product. A well-thought-out strategic development plan is an essential tool for improving efficiency,
reducing costs, shortening timelines, and increasing the probability of success for a new drug program.
A multi-disciplinary project team of experienced experts collaborate in preparing this plan, which
outlines the key nonclinical studies and Phase I-III clinical trials, chemistry, manufacturing and
controls (CMC) and formulation activities, regulatory submissions and health authority interactions,
as well as commercial launch activities and life-cycle management. By identifying potential
development issues and challenges, the strategic plan can include alternative development options or
scenarios that help companies avoid or mitigate risks.
The strategic plan also outlines major development milestones and success criteria and can facilitate
cost and timeline estimates that provide a basis for sound investment decisions and project portfolio
prioritization and management.
The major parts of a comprehensive drug
development strategy include the target
product profile (TPP), and the regulatory,
nonclinical, clinical, manufacturing and
commercial plans. Integrating all of these
elements together in a seamless strategy
document is a critical first step on the road
toward realizing a program’s ultimate goals.
Comprehensive Drug Development Strategy
Regulatory
Nonclinical
Clinical
Commercial
CMC
TPP

2. What Is a Target Product Profile (TPP), and Why Is It Needed?
“If you don’t know where you are going, how will you get there?”
An important first step in creating a strategic roadmap for a drug development program involves clearly
defining a destination that encompasses the key characteristics of the marketed drug product. Internal and
external experts collaborate to outline the desired final product attributes. These include the target indication
or disease(s) to be treated, patient population(s), therapeutic efficacy and clinical safety, formulations, dosing
regimens and administration, drug-drug interactions and contraindications or precautions, among others.
A TPP is a compilation of these characteristics and provides a basis for guiding the design of all program
activities, such as nonclinical and clinical studies, to ensure they will provide the information needed to
assess whether the drug has the desired attributes. Clinical trials and other nonclinical studies will then be
focused to answer critical questions at the earliest possible stages of clinical development. For example, does
the drug have pharmacokinetics that permit once-a-day dosing, or is therapeutic efficacy better than currently
available therapies? Such information provides essential positioning for a competitive drug product.
The TPP also helps set criteria for critical investment decisions. For example, based on initial Phase I and II trial
efficacy and safety results, should the drug candidate be advanced into lengthy, expensive Phase III development?
Creating a TPP brings many questions into sharp focus and drives efficient development program
planning, but the TPP is not a static document. To ensure ongoing development remains on track, the
TPP evolves with new information from clinical trials, nonclinical studies and the external regulatory
and commercial environment. In this way, the TPP eventually provides the basis for preparing the final
approved product label.
For a novel drug candidate that has not yet entered clinical testing,
research scientists may provide only their best estimates of the final
product’s attributes based on nonclinical data. Nonetheless, clinicians
can use the initial TPP to begin assessing how the envisioned drug
product will meet a medical need while commercial experts can begin
to plan where the drug should be marketed, how the drug would fill
a market niche and also attain reimbursement. Regulatory experts
start assessing how health authorities will evaluate the new drug
product and what types of data should be sought in both nonclinical
studies and clinical trials to gain approval. Such initial considerations
guide planning each of the strategic components of the integrated
development plan that are described below.
What Is a Regulatory Strategy, and Why Is It Needed?
Drug regulations can be complicated, and often vary among countries/regions. Regulatory agency
perspectives on development topics can evolve, significantly affecting how a new program should be
designed and executed. A detailed understanding of regulatory requirements and health authority
viewpoints is central to planning a drug development program.
Additional TPP Resources
▶ A TPP template
http://bit.ly/2TlWDUH
▶ Regulatory success with a TPP
http://bit.ly/2RomIQZ

3. A regulatory strategy can include:
▶ The recommended pathway for regulatory approval, based on relevant regulatory guidelines and
precedents from the agencies (e.g., FDA, EMA, PMDA, SFDA) in the market(s) of interest. This can also
include a description of alternative approval pathway options, explaining pros and cons and providing the
rationale for the recommended option.
▶ Regulatory intelligence, such as an evaluation of the regulatory paths taken for similar drugs (if
applicable), whether these drugs were approved (or not), or still in development. A diligent analysis
identifies any special regulatory agency requirements that may apply to a new drug.
▶ A timeline for major regulatory submissions (e.g., IND, NDA/BLA for U.S. FDA and similar filings in
other countries), and additional agency interactions (e.g., pre-IND, and End-of-Phase II meetings) that will
provide feedback to address questions and ensure the program ultimately will meet agency expectations.
▶ Plans for agency interactions, which include the goals and objectives of each major meeting, an outline
of the key questions that need answering, as well as how those questions should be asked.
▶ Key studies and types of trial endpoints and data that regulators will need to see at each stage of drug
development; identification of potential regulatory agency concerns and challenges. This helps insure
nonclinical studies, clinical trials and CMC activities provide the necessary data.
▶ Special options for accelerated review and approval, or market exclusivity that may be applicable to the
drug (e.g., fast-track, breakthrough, orphan disease indication status)
What Is a Clinical Development Strategic Plan?
A carefully planned set of clinical trials, progressing from first-in-human Phase I to Phase II “proof of
concept” and pivotal Phase III trials for registration is a central part of a comprehensive development plan.
Clinical trials are often the most expensive and rate-limiting part of a program, so considerable effort goes
into designing trials that are both necessary and sufficient for regulatory approval and market success.
These trials will also provide the data for making investment and/or partnering decisions at intermediate
points during development.
To begin designing a clinical trial program, physician-scientists first review the preclinical profile of the
new drug candidate (e.g., its pharmacology, mechanism of action and toxicology) and summarize their
assessment of how such properties may impact clinical trial design, as well as proposed therapeutic use in
patients. The medical and scientific rationale for the drug product is assessed to ensure that the marketed
product is likely to gain acceptance by healthcare providers, patients and professional medical organizations.
The clinical plan can include:
▶ Summary outlines of each key trial, from initial Phase I through Phase III, including the study
objectives and clinical hypotheses, trial design, key endpoints and measures (e.g., for safety, efficacy,
pharmacodynamics, pharmacokinetics, surrogate markers, biomarkers and patient-reported outcomes,
etc.), as well as subject populations, key inclusion/exclusion criteria, and approximate subject numbers
and treatment durations. More detailed trial descriptions (e.g., clinical trial protocol synopsis, and
operational feasibility assessments) can also be appended to a development plan, if needed.

4. ▶ A “proof-of-concept” definition. When an early “Go/No-Go” milestone decision is required to decide if
the drug can meet the TPP (e.g., as might be needed for continued investment or to inform partnering/
licensing decisions), a Phase I or II study can often be designed so that results enable a well-founded
decision. The clinical development plan can also provide specific “Go/No-Go” decision criteria.
Articulating and justifying such important criteria can involve detailed consultation with statisticians
and other project team members, as well as senior company management.
▶ Post-approval plans for additional clinical trials and related clinical activities, that can include the following:
∙ Phase IV trials to explore additional therapeutic indications, or to compare a new drug’s effects versus
competing drugs/therapies to demonstrate health economic value and support reimbursement by
insurers, or to evaluate new drug formulations that may provide additional patient convenience or
benefits, or to gain approval for use in special populations (e.g. pediatrics).
∙ Specific commitments made to regulatory agencies as a condition for initial approval (e.g.,
cardiovascular safety trials for diabetes drugs).
∙ Risk Evaluation and Management Strategies (REMS) plans that are sometimes needed following
approval to monitor specific safety concerns and/or meet regulatory pharmacovigilance requirements.
▶ A high-level timeline that helps in coordinating and scheduling other program activities and
triggering financial and resource investments, e.g., for drug manufacturing and scale-up, formulation
development, toxicology and drug metabolism studies, or validation of biomarkers and/or companion
diagnostics, or seeking regulatory agency advice.
▶ An evaluation of any major clinical development issues or risks, including ways to address potential
contingencies or mitigate challenges, with options for modified or alternative development scenarios. Every
drug program is unique, but lessons learned from prior programs (internal and external) can often be applied to
recognize and avoid pitfalls in new programs.
What Is a CMC Strategy, Why Is It
Important, and How Is It Prepared?
Every new drug development program needs a plan for
maintaining adequate drug supplies for each phase of the
program, with a formulation suitable for the intended route
of administration that meets all nonclinical and clinical trial
needs, as well as all regulatory requirements. A CMC plan
functions as a vital component of a fully integrated development
plan by outlining the major features of a drug supply and
formulation strategy, as well as any placebo or comparator
drug supply needs. A CMC plan includes an assessment of the
estimated cost of goods (COGs) for the drug substance and final
market product, a key factor in new drug development.
Components of a CMC Plan
▶ Assessment of any existing drug synthesis,
manufacturing, or scale-up procedures and costs
▶ Plans for quality control, packaging or shipping
▶ Recommendations for future drug production
processes, based on the proposed clinical trials
(considering their timing, size and geographic
location)
▶ Expected demand once the drug is on the market
▶ Drug-specific liabilities (e.g., chemical
instability, or high synthesis costs) that could
jeopardize approval or market success
▶ Recommendations to preclude or mitigate
potential risks

5. Preparing a CMC strategy often begins with a thorough technical, scientific and regulatory review of all
available data on the drug substance or API (active pharmaceutical ingredient). The review also examines
any existing pilot drug formulations to assess whether the available CMC data can be used to support
the proposed nonclinical studies and the clinical trials and can also meet relevant Good Manufacturing
Practices (GMP) regulatory requirements. That review can outline any additional CMC work needed
during development, for example, to ensure drug supply availability, stability and purity, with analytical
methods for quality control that meet required specifications.
What Is the Nonclinical Strategy and Plan?
Advancing a drug into initial Phase I trials requires completing numerous nonclinical studies. These
studies must comply with detailed regulatory guidelines, such as GLP or ICH, and convince regulatory
agencies and oversight committees or review boards that a drug is suitable for administration to people at
the planned dose levels. Nonclinical studies typically include toxicology, genetic toxicology, pharmacology,
safety pharmacology, and drug metabolism and pharmacokinetic and bioanalytical studies, among others.
Later Phase II and III clinical development and regulatory approval for marketing requires additional
nonclinical studies, for example, longer-duration toxicology and reproductive toxicology, and
carcinogenicity, and bio-distribution studies. Special studies may also be needed to address concerns
unique to a specific drug, or its molecular target and mechanism of action.
Preparing the nonclinical strategy begins with a thorough
technical, scientific and regulatory review of all available
nonclinical reports and findings, including in vitro and in
vivo studies. Based on an assessment of whether the available
nonclinical data are scientifically sound and adequate to
support the proposed clinical trials and meets all relevant
regulatory guidelines, the nonclinical plan will recommend
and describe any additional nonclinical studies needed
to support the proposed clinical trial program and final
regulatory approval for marketing.
During this process, the nonclinical expert interacts closely with colleagues in other disciplines. For
example, if a nonclinical in vitro drug metabolism study suggests a drug-drug interaction that might
have significant implications for patient safety, or for commercial viability, a recommendation might be
prepared for conducting a specific drug-drug interaction clinical trial. If the trial is completed during early
development, the results can be used in early Go/No-Go decisions, help aid clinical dose and formulation
selections or inform decisions involving combination drug treatments in later Phase II or III trials.
What Is a Commercial Strategy Plan, and Why Is It Important?
Completing an entire drug development program and obtaining regulatory approval for marketing a new
drug is a major accomplishment, but this does not guarantee commercial success or maximum return
on investment nor ensure optimal opportunity for patients to benefit from the new product. Successfully
penetrating the healthcare market after launch to assure rapid adoption by prescribers and wide use by
patients requires a well-planned commercial strategy that favorably positions the product with key opinion
leaders and stakeholders, including physicians, professional medical organizations and insurers who make
reimbursement decisions.
Important Aspects of a Nonclinical
Strategy
▶ Choice of animal species, and selection of doses
in toxicology studies
▶ Recommendations and rationales for study
designs, and relevance of nonclinical studies
▶ The role and timing for regulatory agency input

6. Planning a commercial strategy begins with a thorough review and analysis of the competitive landscape
for the product against currently available treatments, considering their effectiveness, side effects, costs
and patients’ and physicians’ satisfaction with existing therapeutics, along with upcoming treatments that
are in the pipeline.
This exercise informs how the drug can be differentiated from competitors, what types of data should be
obtained to best demonstrate value and contributes to determining the target drug price, as well as the
economic value (e.g., NPV) of the drug asset. Whether conducted during Phases I-III, or following approval
in Phase IV studies, a competitive landscape analysis can also influence the design of the program’s
clinical trials. For example, before granting reimbursement, insurers can require strong evidence that
an innovative new drug provides patient or health economic benefits that offset its typically higher cost
versus low cost generic drugs. Insurers or payers may also ask, “If the new drug is prescribed together
with another, standard of care treatment, will it provide additional therapeutic benefit?” Being prepared to
answer such questions can make a major difference in market access for the new drug.
A commercial strategy can identify the most important health economic endpoints to include in clinical trials
or suggest how to obtain relevant data via approaches other than traditional interventional clinical trials,
such as real-world evidence based on analyses of patient healthcare databases or pharmaco-epidemiological
studies, which can be used to convincingly demonstrate the drug’s value and justify pricing.
Beyond the initial approval and commercial launch, life-cycle management encompasses ways to extend
and maximize the therapeutic and commercial value of a newly marketed drug. It can include designing
additional development programs for supplemental regulatory approvals, i.e., to market the drug for
other diseases or conditions. A complete commercial strategy that includes such life-cycle strategies
helps companies understand long-term commercial potential and can influence even very early program
investment decisions or partnering considerations.
Formulating a commercial strategy, even at very early stages of planning a drug development program,
can identify critical success factors that might otherwise be overlooked. It can also recommend the best
methods for obtaining relevant data and effectively communicating results to stakeholders to maximize
market access and the value of a new drug product.
Why Is a Clear Roadmap to Market Needed?
Creating a comprehensive development strategy is a smart investment for both established large
pharmaceutical companies and emerging biotechnology companies. The effort of considering and
integrating the many facets of a program in this strategy can help avoid pitfalls that could delay or even kill
a program, and can reduce timelines and development costs and improve the odds of successful regulatory
approvals globally.
A well-thought out development plan that integrates all key activities and demonstrates a clear roadmap
to market not only engenders confidence in a project by senior management – and potential partners –
but also serves as a tool that maximizes the likelihood of successfully bringing the benefits of your new
medicine to patients.
Learn more about our drug development solutions at www.covance.com
Covance Inc., headquartered in Princeton, NJ, USA, is the drug development business of Laboratory
Corporation of America Holdings (LabCorp). COVANCE is a registered trademark and the
marketing name for Covance Inc. and its subsidiaries around the world.
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